生物活性

• 描述Human XPO1 (exportin-1) is the key nuclear-cytoplasmic transport protein which can export many cargo proteins out of the nucleus. Inhibition of XPO1 resulting in nuclear accumulation of these proteins causes cancer cell death. KPT-8602 is a second-generation XPO1 inhibitor with potency against a panel of leukemia cell lines. Compared with the previous selective inhibitor of nuclear export (SINE) compound KPT-330, KPT-8602 demonstrates substantially reduced brain penetration thus resulting its attenuation of the central nervous system mediated side effects of anorexia and weight loss. KPT-8602 inhibited the XPO1 dependent nuclear export with an EC50 value of 60.9nM in HeLa cells stably expressing this GFP reporter protein. Treatment with KPT-8602 at concentration of 0.3 and 1μM overnight caused significantly decreased levels of XPO1 protein by proteolytic degradation mechanism. KPT-8602 induced cytotoxicity with EC50 values ranging in 25-145nM in a panel of leukemia cell lines post 72-hour treatment and induced apoptosis of Jurkat and MOLT-4 T-ALL shown as cleaved PARP as early as 6 hours after treatment at concentration of 1μM. As an important cargo of XPO1, an increased p53 nuclear and upregulation and stabilization of p53 shown by phosphorylated (Ser15) could be observed in MOLT-4 post KPT-8602 treatment. Oral administration of KPT-8602 at dose of 5mg/kg or 15mg/kg, daily, for 19 days, showed potent anti-lymphoblastic leukemia activity in MOLT-4 subcutaneous xenografted mice. Also it prolonged survival of patient derived xenograft models of ALL. A tumor cell-specific 3D nuclear telomere organization is sensitive to XPO1 inhibition by KPT-8602.

• 动物研究
  剂量	Mice: 15 mg/kg[1] (p.o.)
  给药途径	p.o.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02649790	Relapsed/Refractory Multiple M... more >>yeloma (RRMM) Metastatic Colorectal Cancer (mCRC) Metastatic Castration Resistant Prostate Cancer (mCRPC) Higher Risk Myelodysplastic Syndrome (HR-MDS) Collapse <<	Phase 1 Phase 2	Recruiting	June 2019	United States, Florida ... more >> Moffitt Cancer Center Recruiting Tampa, Florida, United States, 33612 Contact: Rachid Baz, MD    813-745-8212    Rachid.Baz@Moffit.org    Principal Investigator: Rachid Baz, MD          United States, New Jersey John Theurer Cancer Center at Hackensack UMC Recruiting Hackensack, New Jersey, United States, 07601 Contact: Noa Biran, MD    551-996-8704    NBiran@HackensackUMC.org    Principal Investigator: Noa Biran, MD          United States, New York Weill Cornell Medical College Recruiting New York, New York, United States, 10021 Contact: Sangmin Lee, MD    646-962-7200    sal9053@med.cornell.edu    Principal Investigator: Sangmin Lee, MD          United States, Ohio Ohio State University, The James Cancer Hospital and Solove Research Institute Recruiting Columbus, Ohio, United States, 43210 Contact: John Hays, MD, PhD       John.Hays@osumc.edu    Principal Investigator: John Hays, MD, PhD          United States, Pennsylvania University of Pennsylvania Abramson Cancer Center Clinical Research Unit Recruiting Philadelphia, Pennsylvania, United States, 19104 Contact: Dan Vogl, MD    215-614-0037    Dan.Vogl@uphs.upenn.edu    Principal Investigator: Dan Vogl, MD          United States, Tennessee Vanderbilt University Medical Center Recruiting Nashville, Tennessee, United States, 37232 Contact: Robert Cornell, MD,MS    615-936-8422    robert.f.cornell@vanderbilt.edu    Principal Investigator: Robert Cornell, MD,MS          Canada, Ontario Princess Margaret Cancer Research Completed Toronto, Ontario, Canada Canada, Quebec MUHC GLEN Site Cedars - Cancer Centre Completed Montréal, Quebec, Canada Collapse <<

• 参考文献

• [1] Etchin J, Berezovskaya A, et al. KPT-8602, a second-generation inhibitor of XPO1-mediated nuclear export, is well tolerated and highly active against AML blasts and leukemia-initiating cells. Leukemia. 2017 Jan;31(1):143-150.

  [2] Hing ZA, Fung HY, et al. Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies. Leukemia. 2016 Dec;30(12):2364-2372.